Loss of interleukin-10 activates innate immunity to eradicate adult T-cell leukemia-initiating cells

Hiba El Hajj; Rita Hleihel; Marwan El Sabban; Julie Bruneau; Ghazi Zaatari; Morgane Cheminant; Ambroise Marçais; Abdou Akkouche; Hideki Hasegawa; William Hall; Hugues De Thé; Olivier Hermine; Ali Bazarbachi

doi:10.3324/haematol.2020.264523

Loss of interleukin-10 activates innate immunity to eradicate adult T-cell leukemia-initiating cells

Haematologica. 2021 May 1;106(5):1443-1456. doi: 10.3324/haematol.2020.264523.

Authors

Affiliations

¹ Department of Internal Medicine, Faculty of Medicine, American University of Beirut, 1107 2020 Beirut, Lebanon; Department of Experimental Pathology, Microbiology and Immunology, Faculty of Medicine, American University of Beirut, 1107 2020 Beirut. he21@aub.edu.lb.
² Department of Internal Medicine, Faculty of Medicine, American University of Beirut, 1107 2020 Beirut.
³ Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, 1107 2020 Beirut.
⁴ Institut Imagine - INSERM U1163, Necker Hospital, University of Paris, 75015 Paris France; Department of Pathology, Necker Hospital, University of Paris, Assistance Publique Hôpitaux de Paris, 75015 Paris.
⁵ Department of Pathology and Laboratory Medicine, Faculty of Medicine, American University of Beirut, 1107 2020 Beirut.
⁶ Institut Imagine - INSERM U1163, Necker Hospital, University of Paris, 75015 Paris France; Department of Hematology, Necker Hospital, University of Paris, Assistance Publique Hôpitaux de Paris, 75015 Paris.
⁷ Department of Hematology, Necker Hospital, University of Paris, Assistance Publique Hôpitaux de Paris, 75015 Paris, France; INSERM UMR 1151, University of Paris, Paris.
⁸ National Institute of Infectious Diseases, 208-0011 Tokyo.
⁹ University College Dublin, 47335 Dublin, Ireland; GI CoRE, Center for Zoonosis Control, Hokkaido University, Sapporo.
¹⁰ INSERM UMR 944, Equipe labellisée par la Ligue Nationale contre le Cancer, Institut Universitaire d'Hématologie, Hôpital St. Louis 1, Avenue Claude Vellefaux 75475 PARIS cedex 10 France; CNRS UMR 7212, Hôpital St. Louis 1, Avenue Claude Vellefaux 75475 PARIS cedex 10 France; College de France, Place Marcelin Berthelot 75005 PARIS France.
¹¹ Institut Imagine - INSERM U1163, Necker Hospital, University of Paris, 75015 Paris France; Department of Hematology, Necker Hospital, University of Paris, Assistance Publique Hôpitaux de Paris, 75015 Paris. ohermine@gmail.com.
¹² Department of Internal Medicine, Faculty of Medicine, American University of Beirut, 1107 2020 Beirut, Lebanon; Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, 1107 2020 Beirut. bazarbac@aub.edu.lb.

Abstract

Adult T cell leukemia/lymphoma (ATL) is associated to chronic human T cell leukemia virus type 1 (HTLV-1) infection and carries a poor prognosis. Arsenic trioxide (AS) and interferon-alpha (IFNα) together selectively trigger Tax viral oncoprotein degradation and cure Tax-driven murine ATL. AS/IFNα/zidovudine treatment achieves a high response rate in patients with chronic ATL. Interleukin 10 (IL-10) is an immuno-suppressive cytokine whose expression is activated by Tax. Here we show that, in ATL, AS/IFNα-induced abrogation of leukemia initiating cell activity requires IL-10 expression shutoff. Loss of IL-10 secretion drives production of inflammatory cytokines by the microenvironment, followed by innate immunity-mediated clearance of Taxdriven leukemic cells. Accordingly, anti-IL-10 monoclonal antibodies significantly increased the efficiency of AS/IFNα therapy. These results emphasize the sequential targeting of malignant ATL cells and their immune microenvironment in leukemia initiating cell (LIC) eradication and provide a strong rational to test AS/IFNα/anti-IL10 combination in ATL.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Animals
Human T-lymphotropic virus 1*
Humans
Immunity, Innate
Interferon-alpha
Interleukin-10 / genetics
Leukemia-Lymphoma, Adult T-Cell* / drug therapy
Mice
Tumor Microenvironment

Substances

IL10 protein, human
IL10 protein, mouse
Interferon-alpha
Interleukin-10

Grants and funding

FundingThis work was supported by the American University of Beirut Medical Practice Plan, the University Research Board, the Lebanese National Council for Scientific Research, the Lady TATA Memorial Trust; the European Research Council (Senior Grant 268729–STEMAPL) (to HdT), the Ligue Nationale Contre le Cancer, Centre National de la Recherche Scientifique, Association de Recherche Contre le Cancer, Institut National Contre le Cancer, and Cancerople Ile de France (to OH).